Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex.
Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex.
复制标题
LNCRNA和新型T-box3共抑制剂复合物对衰老的协调控制。
DOI：
10.7554/elife.02805
复制
发表时间：
2014-05-29
期刊：
影响因子：
7.7
通讯作者：
Moon AM
中科院分区：
文献类型：
--
作者：
Kumar P P;Emechebe U;Smith R;Franklin S;Moore B;Yandell M;Lessnick SL;Moon AM
细胞衰老是一种重要的肿瘤抑制机制。我们发现了一种APPERα/Tbx3抑制物复合体，它是防止原代细胞和小鼠胚胎衰老所必需的。以前未知的CAPERα在控制细胞增殖中的关键作用体现在与Tbx3的强制性相互作用中，以调节染色质结构并抑制CDKN2A-p16INK和Rb途径的转录。IncRNAUCA1是CAPERα/Tbx3抑制的直接靶标，其过度表达足以诱导衰老。在增殖细胞中，我们发现hnRNPA1结合并破坏CDKN2A-p16INK mRNA的稳定，而在衰老过程中，UCA1隔离hnRNPA1，从而稳定CDKN2A-p16INK。因此，CAPERα/Tbx3和UCA1构成了一种协调的、强化的机制，调节CDKN2A-p16INK的转录和mR NA的稳定性。在致癌胁迫过程中，CAPERα/Tbx3共抑制子的解离激活了UCA1，揭示了癌基因诱导衰老的新机制。我们在体内对CAPERα和UCA1功能的阐明为研究衰老诱导以及Tbx3的致癌和发育特性提供了新的视角。DOI：http://dx.doi.org/10.7554/eLife.02805.001细胞的分裂和生长是生存所必需的。但同样重要的是，细胞可以停止分裂，因为如果不这样做，可能会导致癌症中出现的肿瘤生长不受控制。一种这样的质量控制机制被称为衰老，它可以阻止老化、受损或行为可能损害机体的细胞的生长和繁殖。所有细胞最终都会停止分裂并经历衰老，但许多因素可能会提前触发这一过程，如DNA损伤、压力或致癌蛋白质的出现。如果衰老发生得太早，并干扰正常生长，那么它可能是有害的。如果在发育早期不适当地触发衰老，就会发生严重的出生缺陷，包括致命的心脏问题和肢体畸形。编码一种名为TBX3的蛋白质的基因突变与这些严重的出生缺陷有关。正常情况下，TBX3会阻止其他在发育早期触发衰老的蛋白质的产生，并有助于维持成年细胞的稳定状态。了解它是如何做到这一点的，可以帮助科学家了解正常的细胞功能和衰老，也有助于找到触发癌细胞衰老的方法。Kumar等人研究发现，一种名为CAPERα的蛋白质--AP1和雌激素受体的简称协同激活剂--与tbx3形成了一种复合体，可以通过至少两种不同的方式阻止活着的有机体中的细胞分裂。一种方法是改变DNA的折叠方式。另一种方法涉及一种名为UCA1的基因的非编码链RNA：这种RNA可以防止阻止细胞分裂的蛋白质的降解。在正常的增殖细胞中，CAPERα/Tbx3蛋白复合体阻止UCA1RNA的产生。相比之下，在受到致癌刺激的细胞中，Tbx3和CAPERα在物理上是分开的：这激活了UCA1RNA的产生，导致衰老。需要进一步的研究来确定CAPERα/Tbx3蛋白复合体是如何与dna和rna相互作用来控制衰老和预防癌症的。DOI：http://dx.doi.org/10.7554/eLife.02805.002
Cellular senescence is a crucial tumor suppressor mechanism. We discovered a CAPERα/TBX3 repressor complex required to prevent senescence in primary cells and mouse embryos. Critical, previously unknown roles for CAPERα in controlling cell proliferation are manifest in an obligatory interaction with TBX3 to regulate chromatin structure and repress transcription of CDKN2A-p16INK and the RB pathway. The IncRNA UCA1 is a direct target of CAPERα/TBX3 repression whose overexpression is sufficient to induce senescence. In proliferating cells, we found that hnRNPA1 binds and destabilizes CDKN2A-p16INK mRNA whereas during senescence, UCA1 sequesters hnRNPA1 and thus stabilizes CDKN2A-p16INK. Thus CAPERα/TBX3 and UCA1 constitute a coordinated, reinforcing mechanism to regulate both CDKN2A-p16INK transcription and mRNA stability. Dissociation of the CAPERα/TBX3 co-repressor during oncogenic stress activates UCA1, revealing a novel mechanism for oncogene-induced senescence. Our elucidation of CAPERα and UCA1 functions in vivo provides new insights into senescence induction, and the oncogenic and developmental properties of TBX3. DOI: http://dx.doi.org/10.7554/eLife.02805.001 Cell division and growth are essential for survival. But it is equally important that cells can stop dividing, because failing to do so can lead to the uncontrolled tumor growth seen in cancer. One such quality control mechanism is called senescence, which stops the growth and multiplication of cells that are old, damaged or behaving in ways that may harm the organism. All cells eventually stop dividing and undergo senescence, but a number of factors may trigger the process early, such as DNA damage, stress or the appearance of cancer-causing proteins. Senescence can be harmful if it occurs too early in life and interferes with normal growth. Severe birth defects—including fatal heart problems and limb malformations—occur if senescence is inappropriately triggered early in development. Mutations in a gene encoding a protein called TBX3 have been linked to these severe birth defects. Normally, TBX3 stops the production of other proteins that trigger senescence in early development, and helps to maintain stable conditions in adult cells. Understanding how it does so could help scientists understand normal cell function and aging, and also help to find ways to trigger senescence in cancerous cells. Kumar et al. found that a protein called CAPERα—for short Coactivator of AP1 and Estrogen Receptor—forms a complex with TBX3 that stops cells dividing in living organisms in at least two different ways. One way is by altering how DNA is folded. The other way involves a non-coding strand of RNA from a gene called UCA1: this RNA prevents the degradation of proteins that stop cell division. In normal proliferating cells, the CAPERα/TBX3 protein complex prevents the production of UCA1 RNA. In contrast, in cells that received a cancer causing stimulus, TBX3 and CAPERα physically separate: this activates production of UCA1 RNA and causes senescence. Further studies will be required to establish exactly how the CAPERα/TBX3 protein complex interacts with DNA and RNA to control senescence and prevent cancer. DOI: http://dx.doi.org/10.7554/eLife.02805.002